Bronchial asthma is a pathological symptom, in which airway is contracted by airway contraction and inflammation, causing paroxysmal cough, stridor, and breathing difficulty. The drugs for it include steroidal agents for inhalation, which have a strong antiinflammatory effect, β stimulants and theophyllines which are bronchodilating agents, antiallergic agents which inhibit the effect of mediators, etc.
It is known that various chemical mediators are involved in bronchial asthma, among which cysteinyl leukotrienes (cysLTs) are known to have approximately 1000 times stronger contractile effect on airway as compared to histamine. Moreover, cysLTs promote induction of airway inflammation, typically inflammation cell invasion, airway hypersensitivity and mucus secretion in airway, and they are deeply involved in basic pathology of bronchial asthma.
CysLTs are a physiological active substance in a live body, which is a metabolic product from arachidonic acid by 5-lipoxygenase. CysLTs have at least two types of receptors, and cysLT1 receptor and cysLT2 receptor have been cloned so far (Nature, 399, 789-793, 1999, J. Biol., Chem., 275, 30531-30536, 2000). CysLT1 receptor is mainly expressed in airway smooth muscle and it is deeply concerned with the development of bronchial asthma (Am. J. Respir. Crit. Care Med., 163, 226-233, 2001). Those leukotriene (LT) receptor antagonists which are now placed on the market, e.g. pranlukast hydrate, montelukast sodium and zafirlukast, and are selective cysLT1 receptor antagonist (Nature, 399, 789-793, 1999), are useful agents for the treatment of bronchial asthma, which improves various kinds of symptoms and respiratory functions. However, it is known the LT receptor antagonists placed on the market are more effective for mild or moderate symptoms than for severe symptoms. It is also known that there exist some non-responders with mild or moderate symptoms on whom the pharmaceutical agent does not have effect.
On the other hand, it is reported that the ligands for the newly cloned cysLT2 receptor are LTC4, LTD4 and LTE4, and cysLT2 receptor is expressed in the bronchial smooth muscle like CysLT1 receptor (J. Biol. Chem., 275, 30531-30536, 2000, Am. J. Respir. Crit. Care Med., 164, 2098-2101, 2001). However, the functions and roles of cysLT2 receptor in the pathological conditions have not been elucidated yet.
Therefore, provided that cysLT2 receptor, as well as cysLT1 receptor, is concerned with contraction of bronchial smooth muscle, airway inflammation, reactive airway disease and mucus secretion in airway, by antagonizing cysLT2 receptor, it is conceivably possible to produce an agent for respiratory diseases which is more useful than existing LT receptor antagonists. For example, it is expected that such agent shows an efficacy on more severe bronchial asthma patients and non-responders of existing LT receptor antagonist. Moreover, it is also reported that cysLT2 receptor is expressed in heart, brain and peripheral blood leukocyte, etc. in addition to bronchial smooth muscle (J. Biol. Chem., 275, 30531-30536, 2000). Therefore, cysLT2 receptor antagonists are expected to be agents for the treatment of cardiovascular, central nervous system and various inflammatory diseases.
In Molecular Pharmacology (United States), 2000, 58, p. 1601-1608, it is disclosed that a compound of formula (A)
antagonizes both cysLT1 and cysLT2.
And in the gazette of JP9-169712, it is disclosed that a benzoic acid derivative of formula (B)
wherein, R1B is hydrogen, alkyl having up to 6 carbons, or substituted phenyl; PB and QB is each oxygen, sulfur or a bond; XB is oxygen, sulfur or —CONH—; TB is ethylene, oxygen, sulfur or a bond; YB is —COOH, —NHSO2R3B or CONHSO2R3B; ZB is —COOH, COR4B, —CO(CH2)pBCO2H, —O(CH2)pBCO2H, —S(CH2)pBCO2H, NO2, —CONHWBCO2H or NHWBCO2H; mB is an integer from 0 to 6; and nB is an integer from 0 to 4 shows leukotriene antagonistic action, that is effective for the treatment of respiratory diseases, and that it antagonizes both cysLT1 receptor and cysLT2 receptors.
Also, in the program of the 98th American Thoracic Society (2002, D38, F4) it is described that DUO-LT, which is a compound whose clinical target is ischemic diseases and inflammatory diseases, antagonizes both cysLT1 and cysLT2 receptors.
In the specification of WO 2004/052839, it is disclosed that a compound of formula (C)
wherein all symbols have the same meaning as described in the specification, has an antagonizing effect against CysLT2 receptors and the compound is useful for the treatment and/or prevention of cardiovascular diseases such as angina pectoris, cardiac infarction, etc.